Pharmaceutical composition containing fenofibrate and method for the preparation thereof

ABSTRACT

The invention concerns a pharmaceutical composition containing micronized fenofibrate, a surfactant and a binding cellulose derivative, as solubilizing adjuvant, preferably hydroxypropylmethylcellulose. The cellulose derivative represents less than 20 wt. % of the composition. The association of micronized fenofibrate with a binding cellulose derivative, as solubilizing adjuvant and a surfactant enables enhanced bioavailability of the active principle. The invention also concerns a method for preparing said composition without using any organic solvent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 11/509,806,filed Aug. 25, 2006, which is a continuation of application Ser. No.10/030,262, filed Apr. 17, 2002, now U.S. Pat. No. 7,101,574 which is aNational Stage of Application No. PCT/FR00/01971, filed Jul. 7, 2000,which claims the benefit of French Application No. 99/08,923, filed onJul. 9, 1999.

The present invention relates to a novel pharmaceutical compositioncontaining fenofibrate.

Fenofibrate is recommended in the treatment of adult endogenoushyperlipidemias, of hypercholesterolemias and of hypertriglyceridemias.A treatment of 300 to 400 mg of fenofibrate per day enables a 20 to 25%reduction of cholesterolemia and a 40 to 50% reduction oftriglyceridemia to be obtained.

The major fenofibrate metabolite in the plasma is fenofibric acid. Thehalf-life for elimination of fenofibric acid from the plasma is of theorder of 20 hours. Its maximum concentration in the plasma is attained,on average, five hours after ingestion of the medicinal product. Themean concentration in the plasma is of the order of 15 micrograms/ml fora dose of 300 mg of fenofibrate per day. This level is stable throughouttreatment.

Fenofibrate is an active principle which is very poorly soluble inwater, and the absorption of which in the digestive tract is limited. Anincrease in its solubility or in its rate of solubilization leads tobetter digestive absorption.

Various approaches have been explored in order to increase the rate ofsolubilization of fenofibrate: micronization of the active principle,addition of a surfactant, and comicronization of fenofibrate with asurfactant.

Patent EP 256 933 describes fenofibrate granules in which thefenofibrate is micronized in order to increase its bioavailability. Thecrystalline fenofibrate microparticles are less than 50 μm in size. thebinder used is polyvinylpyrrolidone. The document suggests other typesof binder, such as methacrylic polymers, cellulose derivatives andpolyethylene glycols. The granules described in the examples of EP 256933 are obtained by a method using organic solvents.

Patent EP 330 532 proposes improving the bioavailability of fenofibrateby comicronizing it with a surfactant, such as sodium lauryl sulfate.The comicronizate is then granulated by wet granulation in order toimprove the flow capacities of the powder and to facilitate thetransformation into gelatin capsules. This comicronization allows asignificant increase in the bioavailability compared to the use offenofibrate described in EP 256 933. The granules described in EP 330532 contain polyvinylpyrrolidone as a binder.

This patent teaches that the comicronization of fenofibrate with a solidsurfactant significantly improves the bioavailability of the fenofibratecompared to the use of a surfactant, of micronization or of thecombination of a surfactant and of micronized fenofibrate.

Patent WO 98/31361 proposes improving the bioavailability of thefenofibrate by attaching to a hydrodispersible inert support micronizedfenofibrate, a hydrophilic polymer and, optionally, a surfactant. Thehydrophilic polymer, identified as polyvinyl-pyrrolidone, represents atleast 20% by weight of the composition described above.

This method makes it possible to increase the rate of dissolution of thefenofibrate, and also its bioavailability. However, the preparationmethod according to that patent is not entirely satisfactory since itrequires the use of a considerable amount of PVP and of the otherexcipients. The example presented in that patent application refers to acomposition containing only 17.7% of fenofibrate expressed as a massratio. This low mass ratio for fenofibrate leads to a final form whichis very large in size, hence a difficulty in administering the desireddose of fenofibrate, or the administration of two tablets.

In the context of the present invention, it has been discovered that theincorporation of a cellulose derivative, used as a binder andsolubilization adjuvant, into a composition containing micronizedfenofibrate and a surfactant makes it possible to obtain abioavailability which is greater than for a composition containing acomicronizate of fenofibrate and of a surfactant.

A subject of the present invention is therefore a pharmaceuticalcomposition containing micronized fenofibrate, a surfactant and abinding cellulose derivative, which is a solubilization adjuvant,preferably hydroxypropylmethylcellulose (HPMC).

The composition of the invention is advantageously provided as gelatincapsules containing powder or granules, preferably in the form ofgranules. These granules may in particular be prepared by assembly onneutral microgranules, by spraying an aqueous solution containing thesurfactant, the solubilized binding cellulose derivative and themicronized fenofibrate in suspension, or by wet granulation of powder,according to which the constituents, including in particular themicronized fenofibrate, the surfactant and the cellulose derivative, aregranulated by wet granulation using an aqueous wetting solution, driedand calibrated.

The pharmaceutical composition according to the present invention has ahigh proportion of fenofibrate; it may therefore be provided in aformulation which is smaller in size than the formulations of the priorart, which makes this composition according to the invention easy toadminister.

The amount of fenofibrate is greater than or equal to 60% by weight,preferably greater than or equal to 70% by weight, even more preferablygreater than or equal to 75% by weight, relative to the weight of thecomposition.

In the context of the present invention, the fenofibrate is notcomicronized with a surfactant. On the contrary, it is micronized aloneand then combined with a surfactant and with the binding cellulosederivative, which is a solubilization adjuvant.

The surfactant is chosen from surfactants which are solid or liquid atroom temperature, for example sodium lauryl sulfate, POLYSORBATE® 80 orMONTANE® 20, preferably sodium lauryl sulfate.

The fenofibrate/HPMC ratio is preferably between 5/1 and 15/1.

The surfactant represents between 1 and 10%, preferably between 3 and5%, by weight relative to the weight of fenofibrate.

The binding cellulose derivative represents between 2 and 15%,preferably between 5 and 12%, by weight of the composition.

Hydroxypropylmethylcellulose is preferably chosen, the apparentviscosity of which is between 2.4 and 18 cP, and even more preferablybetween 2.4 and 3.6 cP, such as for example PHARMACOAT 603®.

The mean size of the fenofibrate particles is less than 15 μm,preferably 10 μm, even more preferably less than 8 μm.

The composition of the invention may also contain at least one excipientsuch as diluents, for instance lactose, antifoaming agents, for instanceDIMETHICONE® and SIMETHICONE®, or lubricants, for instance talc.

The pharmaceutical composition of the invention advantageously consistsof granules in an amount equivalent to a dose of fenofibrate of between50 and 300 mg, preferably equal to 200 mg.

The present invention also relates to a method for preparing the powderor the granules, the composition of which is described above. Thismethod uses no organic solvent.

According to a first variant, the granules are prepared by assembly onneutral microgranules.

The neutral microgranules have a particle size of between 200 and 1 000microns, preferably between 400 and 600 microns.

The assembly is carried out in a sugar-coating pan, in a perforatedcoating pan or in a fluidized airbed, preferably in a fluidized airbed.

The assembly on neutral microgranules is carried out by spraying anaqueous solution containing the surfactant, the solubilized bindingcellulose derivative, and the micronized fenofibrate in suspension.

According to a second variant, the granules are obtained by wetgranulation of powder. The granulation enables the powders to be madedense and makes it possible to improve their flow properties. It alsoallows better preservation of the homogeneity, by avoiding the variousconstituents becoming unmixed.

The micronized fenofibrate, the surfactant, the cellulose derivativeand, optionally, the other excipients are mixed, granulated, dried andthen calibrated. The wetting solution may be water or an aqueoussolution containing the binding cellulose derivative and/or thesurfactant.

According to a particular embodiment, the fenofibrate and the otherexcipients are mixed in a planetary mixer. The wetting solution is addeddirectly to the mixture. The wet mass obtained is granulated with anoscillating granulator, and then dried in an oven. The granules areobtained after passage over an oscillating calibrator.

FIG. 1 represents the in vivo release profile of the formulation ofexample 1C and of a formulation of the prior art in fasting individuals.

FIG. 2 represents the in vivo release profile of the formulation ofexample 1C and of a formulation of the prior art in individuals who havejust eaten.

FIG. 3 represents the in vivo release profile of the formulation ofexample 2B and of a formulation of the prior art in fasting individuals.

FIG. 4 represents the in vivo release profile of the formulation ofcomparative example 3 and of a formulation of the prior art inindividuals who have just eaten.

The invention is illustrated in a nonlimiting way by the followingexamples.

EXAMPLE 1 Granules

1A) Microgranules (XFEN 1735)

The microgranules are obtained by spraying an aqueous suspension ontoneutral cores. The composition is given in the following table:

Formula Amount (percentage by mass) Micronized fenofibrate 64.5 Neutralmicrogranules 21 HPMC (Pharmacoat 603 ®) 11.2 Polysorbate ® 80 3.3Fenofibrate content 645 mg/g

The in vitro dissolution was determined according to a continuous flowcell method with a flow rate of 8 ml/min of sodium lauryl sulfate at 0.1N. The percentages of dissolved product as a function of time, incomparison with a formulation of the prior art, LIPANTHYL 200 M, aregiven in the following table.

Time (min) 15 30 Example 1A (% dissolved) 73 95 Lipanthyl 200 M (%dissolved) 47.3 64.7

Formulation 1A dissolves more rapidly than LIPANTHYL 200 M.

1B) Microgranules (X FEN 1935)

The mean size of the fenofibrate particles is equal to 6.9±0.7 microns.

The microgranules are obtained by spraying an aqueous suspension ontoneutral cores. The suspension contains micronized fenofibrate, sodiumlauryl sulfate and HPMC.

The assembly is carried out in a Huttlin fluidized airbed (rotoprocess).

The formula obtained is given below.

FORMULA AMOUNT (percentage by mass) Micronized fenofibrate 65.2 Neutralmicrogranules 20.1 HPMC (Pharmacoat 603 ®) 11.4 Sodium lauryl sulfate3.3 Fenofibrate content 652 mg/g

The size of the neutral microgranules is between 400 and 600 μm.

1C) Gelatin Capsules of Microgranules (Y FEN 001)

Microgranules having the following composition are prepared:

RAW MATERIALS AMOUNT (percentage by mass) Micronized fenofibrate 67.1Neutral microgranules 17.2 Pharmacoat 603 ® (HPMC) 11.7 Sodium laurylsulfate 3.3 35% dimethicone emulsion 0.2 Talc 0.5 Fenofibrate content671 mg/gaccording to the method described in paragraph 1A).

The microgranules obtained are distributed into size 1 gelatin capsules,each containing 200 mg of fenofibrate.

The in vitro dissolution is determined according to a continuous flowcell method with a flow rate of 8 ml/min of sodium lauryl sulfate at 0.1N. The comparative results with a formulation of the prior art,LIPANTHYL 200 M, are given in the following table.

Time (min) 15 30 Example 1C (% dissolved) 76 100 Lipanthyl 200 M (%dissolved) 47.3 64.7

Formula 1C dissolves more rapidly than LIPANTHYL 200 M.

The gelatin capsules are conserved for 6 months at 40° C./75% relativehumidity. The granules are stable under these accelerated storageconditions. In vitro dissolution tests (in continuous flow cells with aflow rate of 8 ml/min of sodium lauryl sulfate at 0.1 N) were carriedout. The percentages of dissolved product as a function of time forgelatin capsules conserved for 1, 3 and 6 months are given in thefollowing table.

Conservation time 1 month 3 months 6 months Dissolution (% dissolved (%dissolved (% dissolved time (min) product) product) product) 5 25.1 23.020.1 15 71.8 65.6 66.5 25 95.7 88.7 91.0 35 104.7 98.7 98.2 45 106.4100.2 99.1 55 106.7 100.5 99.5 65 106.8 100.6 99.7

The evolution of the content of active principle during storage is givenin the following table.

Conservation time 0 1 month 3 months 6 months Content 208.6 192.6 190.8211.7 (mg/gelatin Capsule)Pharmacokinetic Study Carried Out in Fasting Individuals

The in vivo release profile of the gelatin capsules containing the YFEN01 granules at a dose of 200 mg of fenofibrate is compared with that ofthe gelatin capsules marketed under the trademark LIPANTHYL 200 M.

This study is carried out in 9 individuals. Blood samples are taken atregular time intervals and fenofibric acid is assayed.

The results are given in the following table and FIG. 1.

Pharmacokinetic parameters Lipanthyl 200M Example 1C AUC_(0-t) 76 119(μg · h/ml) AUC_(inf) 96 137 (μg · h/ml) C_(max) 2.35 4.71 (μg/ml)T_(max) 8.0 5.5 (hours) Ke 0.032 0.028 (1/hour) Elim ½ 26.7 24.9 (hours)

The following abbreviations are used in the present application:

C_(max): maximum concentration in the plasma,

T_(max): time required to attain the Cmax,

Elim_(1/2): plasmatic half-life,

AUC_(0-t): area under the curve from 0 to t,

AUC_(0-∞): area under the curve from 0 to ∞,

Ke: elimination constant.

The results obtained for LIPANTHYL 200 M and for the product of example1C are represented on FIG. 1 by curves 1 and 2, respectively.

These results show that the composition according to the presentinvention has a bioavailability which is greater than that of LIPANTHYL200 M in fasting individuals.

Pharmacokinetic Study Carried Out in Individuals Who have Just Eaten

The in vivo release profile of the gelatin capsules containing the YFEN01 granules at a dose of 200 mg of fenofibrate is compared with that ofthe gelatin capsules marketed under the trademark LIPANTHYL 200 M.

This study is carried out in 18 individuals. Blood samples are taken atregular time intervals and fenofibric acid is assayed.

The results are given in the following table and FIG. 2.

Pharmacokinetic parameters Lipanthyl 200M Example 1C AUC_(0-t) 244 257(μg · h/ml) AUC_(inf) 255 270 (μg · h/ml) C_(max) 12 13 (μg/ml) T_(max)5.5 5.5 (hours) Ke 0.04 0.04 (1/hour) Elim ½ 19.6 19.3 (hours)

The results obtained for LIPANTHYL 200 M and for the product of example1C are represented on FIG. 2 by curves 1 and 2, respectively.

These results show that the composition according to the presentinvention is bioequivalent to that of LIPANTHYL 200 M in individuals whohave just eaten.

EXAMPLE 2 Powder

2A) Granules (X FEN 1992)

Granules having the following composition are prepared

FORMULA PERCENTAGE BY MASS Micronized fenofibrate 71 Lactose 21.5 HPMC(Pharmacoat 603 ®) 5 Sodium lauryl sulfate 2.5

The micronized fenofibrate, the HPMC and the lactose are mixed using aplanetary mixer. This mixture is granulated in the presence of asolution of sodium lauryl sulfate.

The flow time of the granules is 7 s. The compacting capacity and theparticle size distribution are given in the following tables. Thesemeasurements were carried out in accordance with the standards of theEuropean Pharmacopoeia.

Compacting capacity (X FEN 1992) V0 204 ml V10 186 ml V500 168 ml V1250164 ml V10-V500  22 ml

Particle size distribution (X FEN 1992) Sieve mesh size (mm) % ofoversize mass 0.6 8 0.5 9 0.355 12 0.2 30 0.1 23 0 182B) Gelatin Capsules of Granules (Y FEN 002)

Preparation

The micronized fenofibrate is mixed in a PMA mixer (Niro Fielder) withlactose and HPMC, and then wetted with an aqueous solution of sodiumlauryl sulfate. The mass obtained is granulated by passage over anoscillating granulator, dried and then calibrated on a sieve with a meshsize of 1.25 mm.

The granules are then packaged in size 1 gelatin capsules at doses of200 mg of fenofibrate.

Granules of the following composition are obtained.

PERCENTAGE FORMULA BY MASS Micronized fenofibrate 70 Lactose 21.5Pharmacoat 603 ® (HPMC) 5 Sodium lauryl sulfate 3.5 Content 700 mg/g

Properties of the Granules

The flow time of the granules is 6 s. The compacting capacity and theparticle size distribution are given in the following tables. Thesemeasurements were carried out in accordance with the standards of theEuropean Pharmacopoeia.

Compacting capacity (Y FEN 002) V0 216 ml V10 200 ml V500 172 ml V1250170 ml V10-V500  28 ml

Particle size distribution (Y FEN 002) Sieve mesh size (mm) % ofoversize mass 0.6 5 0.5 7 0.355 11 0.2 30 0.1 25 0 22

The in vitro dissolution is determined according to a continuous flowcell method with a flow rate of 8 ml/min of sodium lauryl sulfate at 0.1N. The comparative results for a formulation of the prior art, LIPANTHYL200 M, are given in the following table.

Time (min) 15 30 Example 2B (% dissolved) 82.2 88.5 Lipanthyl 200M (%dissolved) 47.3 64.7

Formulation 2B dissolves more rapidly than Lipanthyl 200 M.

Stability Tests

The gelatin capsules conserved at 40° C./75% relative humidity arestable for 6 months.

In vitro dissolution tests (in continuous flow cells with a flow rate of8 ml/min of sodium lauryl sulfate at 0.1 N) were carried out. Thepercentages of dissolved product as a function of time for gelatincapsules conserved for 1, 3 and 6 months are given in the followingtable.

Conservation time 1 month 3 months 6 months Dissolution (% dissolved (%dissolved (% dissolved time (min) product) product) product) 5 54.2 52.949.0 15 81.1 75.8 82.2 25 86.4 79.6 87.2 35 88.8 81.6 89.8 45 90.7 82.991.5 55 92.1 83.9 92.7 65 93.2 84.7 93.6

The evolution of the content of active principle during storage is givenin the following table.

Conservation time 0 1 month 3 months 6 months Content 196.6 190.0 199.8203.3 (mg/gelatin capsule)Pharmacokinetic Study Carried Out in Fasting Individuals

The in vivo release profile of the gelatin capsules containing the YFEN002 granules at doses of 200 mg of fenofibrate is compared with that ofthe gelatin capsules marketed under the trademark LIPANTHYL 200 M.

This study is carried out in 9 individuals. Blood samples are taken atregular time intervals and fenofibric acid is assayed.

The results are given in the following table and FIG. 3.

Pharmacokinetic parameters Lipanthyl 200M Example 2B AUC_(0-t) 76 70 (μg· h/ml) AUC_(inf) 96 82 (μg · h/ml) C_(max) 2.35 2.8 (μg/ml) T_(max) 8.05.5 (hours) Ke 0.032 0.033 (1/hour) Elim ½ 26.7 23.1 (hours)

The results obtained for LIPANTHYL 200 M and for the product of example2B are represented on FIG. 3 by curves 1 and 2, respectively.

These results show that the composition of example 2B is bioequivalentto that of LIPANTHYL 200 M in fasting individuals.

COMPARATIVE EXAMPLE 3 Batch ZEF 001

This example illustrates the prior art.

It combines micronization of fenofibrate and the use of a surfactant. Itdiffers from the present invention by the use of the mixture of bindingexcipients consisting of a cellulose derivative other than HPMC: AvicelPH 101 and polyvinylpyrrolidone (PVP K30).

It is prepared by extrusion-spheronization.

Theoretical Formula

Products Theoretical amount (%) Micronized fenofibrate 75.08 Montanox80 ® 4.72 Avicel PH 101 ® 5.02 PVP K 30 ® 4.12 Explotab ® 11.06

In Vitro Dissolution Profile

The in vitro dissolution is determined according to a continuous flowcell method with a flow rate of 8 ml/min of sodium lauryl sulfate at 0.1N. The comparative results with LIPANTHYL 200 M are given in thefollowing table.

Time (min) 15 30 Example 3 (% dissolved) 24 40 Lipanthyl 200M (%dissolved) 47.3 64.7

The dissolution is slower than that observed for LIPANTHYL 200 M.

Pharmacokinetic Study Carried Out in Fasting Individuals

The in vivo release profile of the gelatin capsules containing the ZEF001 granules at doses of 200 mg of fenofibrate is compared with that ofthe gelatin capsules marketed under the trademark LIPANTHYL 200 M.

This study is carried out in 5 fasting individuals receiving a singledose. Blood samples are taken at regular time intervals and fenofibricacid is assayed.

The results are given in the following table and FIG. 4.

Pharmacokinetic parameters Lipanthyl 200M Example 3 AUC_(0-t) 92 47 (μg· h/ml) AUC_(inf) 104 53 (μg · h/ml) C_(max) 3.5 1.7 (μg/ml) T_(max) 5.64.6 (hours) Ke 0.04 0.038 (1/hour) Elim ½ 18.9 20.3 (hours)

The results obtained for LIPANTHYL 200 M and for the product of example3 are represented on FIG. 4 by curves 1 and 2, respectively.

These results show the greater bioavailability of LIPANTHYL 200 Mcompared with this formulation based on the prior art.

Example 3 shows that combining the knowledge of the prior art (namelymicronization or use of surfactants) does not make it possible to obtainrapid dissolution of fenofibrate. This results in low bioavailabilitycompared with LIPANTHYL 200 M.

The compositions prepared according to the present invention show morerapid dissolution than the formula of the prior art and improvedbioavailability.

The invention claimed is:
 1. A pharmaceutical composition comprisingbetween 50 and 300 mg of micronized fenofibrate coated on neutralmicrogranules in a single active layer comprising said micronizedfenofibrate, as surfactant and hydroxypropyl methyl cellulose (HPMC),wherein the fenofibrate/HPMC ratio is between 5/1 and 15/1 and thesurfactant represents between 1 and 10% by weight relative to the weightof fenofibrate.
 2. The composition of claim 1 in a capsule.
 3. Thecomposition of claim 1, wherein the dose of fenofibrate is 50 mg to 200mg.
 4. The composition of claim 1, wherein the neutral microgranuleshave a particle size between 200 and 1000 microns.
 5. The composition ofclaim 4, wherein the neutral microgranules have a particle size between400 and 600 microns.
 6. The composition of claim 1, wherein the meansize of the fenofibrate micronized particles is less than 8 μm.
 7. Thecomposition of claim 1, wherein the surfactant is sodium laurylsulphate.
 8. The composition of claim 1, wherein HPMC represents between3 and 5% by weight relative to the weight of fenofibrate.
 9. Thepharmaceutical composition of claim 1, which, when administered to apatient in a fasting state at a dose of 200 mg fenofibrate, achieves aCmax of at least 4 micrograms/ml.
 10. The pharmaceutical composition ofclaim 1, which, when administered to a patient in a fasting state at todose of 200 mg fenofibrate, achieves AUC of at least
 119. 11. Thepharmaceutical composition of claim 1, wherein at least 20% of saidfenofibrate is dissolved at 5 minutes, as measured using a continuousflow cell method with a flow rate of 8 ml/min of sodium lauryl sulfateat 0.1 N.
 12. The pharmaceutical composition of claim 1, wherein atleast 65% of said fenofibrate is dissolved at 15 minutes, as measuredusing a continuous flow cell method with a flow rate of 8 ml/min ofsodium lauryl sulfate at 0.1 N.